Abstract
BACKGROUND: Aggressive meningiomas (WHO grade II/III) are incurable brain tumors without approved systemic treatment options. Hippo signaling pathway has been shown to be dysregulated in 40-60% of meningioma, resulting in activation of its target YAP and TEAD as transcriptional factors. Here, we investigated the effect of VT3989, a potent TEAD inhibitor, in meningioma cell lines with NF2 alterations. METHODS: Dose response assays were performed with various concentration of VT3989 for 3-5 days and cell growth was measured with CellTiter-glo across several meningioma patient-derived cell lines. Bulk-RNA sequencing was performed on two meningioma cell lines MG309 and IOMM-LEE, following treatment with varying doses of VT3989. Global transcriptomic changes were examined using established QIAGEN CLC Genomics Workbench to identify key molecular pathway changes. Relative expression of TEAD direct targets, DNA damage repair (DDR) genes and cell cycle were quantified using qPCR. Additionally, radiation sensitization effect of VT3989 in meningioma cell lines was tested in vitro. RESULTS: Meningioma cell line MG309 (NF2 loss) was more sensitive to VT3989 (IC50 50 nM), than IOMM-Lee cells (NF2-wild-type) (IC50 30 µM). Transcriptomic analysis identified that canonical downstream targets of TEAD (CTGF, CYR61, and ANKRD1) were significantly downregulated in both MG309 and IOMM-Lee cells after VT3989 treatment. However, MG309 cells but not IOMM-LEE cells showed downregulation of cell cycle regulation, kinetochore signaling and DDR related genes. Consistently, qPCR confirmed these findings in MG309 cells. VT3989 showed synergistic effects with radiation in vitro in both cell-lines. CONCLUSION: Meningioma cells harboring NF2 loss exhibited higher sensitivity and a more robust response to VT3989 compared to NF2 wild-type cells. Evaluation of VT3989 in ex-vivo treated patient tissue samples and PDX mouse models is ongoing.